Consensus Report 1997

Guidelines for the Optimal Care of Boys with
Duchenne Muscular Dystrophy

Consensus Report based on the Proceedings
of an Expert Meeting in Rotterdam, 7 and 8 November 1997

Foreword

The European branch of the Duchenne Parent Project under the leadership of Ms. Elizabeth Vroom (Amsterdam) organized the first European meeting of experts and parents with Duchenne children in Rotterdam on 7 and 8 November 1997. One of the aims of this meeting, chaired by Professor Victor Dubowitz (London), was to get parents and experts together so that the newest developments in research for a rational cure of Duchenne muscular dystrophy and the management of their sons, could be explained to them directly. The papers by the experts and the discussions which followed have been summarized in a report published in the scientific journal Neuromuscular Disorders in May 1998 (volume 8, pages 213-219). Another aim was the development of a consensus report to be used by parents and their family doctors, which was based on this summary and further information and thus would be an international care standard or guidelines for the optimal medical and social treatment of Duchenne children.

The text of this brochure constitutes these guidelines as of the scientific and medical knowledge of 1998. The experts who participated in the Rotterdam meeting worked together and authorized this text thus making it a true international consensus document. Two earlier consensus reports were developed after international expert meetings in the village of Saig in the Black Forest in 1980 and at the University of Aachen in Germany in 1989. Hence, this report is the third, updated and more comprehensive, document destined to help Duchenne families and their doctors to care in the best way for their handicapped sons.

Introduction and Basic Information

How to use the guidelines. These Guidelines are full of instructions of what to do and what not to do with boys and young men who have the still incurable hereditary disease Duchenne muscular dystrophy. The enumeration of such instructions may make these guidelines look like the description of an imperfect technical object which has to be maintained running as long as possible in spite of its structural defects. However, Duchenne boys are human beings, they are children at the beginning and young adults later who have a life perspective which is not predetermined but depends to a large extent on the way the disease is met with actions based on decisions by the human being himself. From as early as possible the child should be treated as an individual person, not as an object, by parents and his medical and social advisers. From an early age, he can take part in making decisions on what is good for him and what should be avoided, provided the problems are explained to him in an understanding and compassionate way.

It is important that the boys understand and accept responsibility for their own life as early as possible. They themselves are partners of the experts, and their wishes and decisions are to be taken seriously from the beginning and not only after reaching adulthood when they are legally empowered to make all their decisions on their own.

The guidelines present the knowledge and opinions of many experts as they were believed to be accurate in the first months of 1998. In the course of time, the facts will change, research will progress, more and better management methods will become available, and the whole outlook may change. This means, that these guidelines will have to be updated from time to time.

The chapters of this brochure are grouped according to the different stages of the disease, however, their age ranges may vary for individual Duchenne boys. The topics discussed in each chapter are those that pertain mainly to that particular stage, but many of these topics are important for more than one disease stage. Some basic information precedes the stage-specific discussions in this introductory chapter.

Clinical course. Duchenne muscular dystrophy is a hereditary disease which affects mainly boys. In general, the first clinical symptoms become obvious when they are about 18 months to three years old: general muscle weakness resulting in a delayed ability to walk, problems to get up from the floor, clumsiness while walking, difficulties climbing stairs, abnormally enlarged calves, and even weakness in their hands. At about 5 to 6 years, contractures or stiffness develop in the foot, knee and hip joints. The progressing muscle wasting leads at about 9 to 12 years to the loss of the walking ability. Orthopaedic operations can delay the contractures and prolong ambulation with long leg braces or calipers. When walking becomes too difficult, the electric wheelchair helps the child to regain and maintain mobility. If necessary and desired by the boy and his parents, a progressive scoliosis or spine deformation can be corrected surgically, and breathing difficulties can be overcome first by intermittent and later, at about 20 to 25 years, by continuous mechanical ventilation.

The development of optimal management methods, especially of long-term mechanical ventilation, has increased the life expectancy of Duchenne boys from about 15 years in the 1960s to up to 30 and in some cases to 40 years or more. However, even now, some of the young men die before they are 20 years old due mainly to cardiac complications which cannot always be overcome even with the most modern methods.

Mental retardation. Many Duchenne boys have normal intelligence. However, dystrophin, the protein missing in Duchenne muscles, seems also to be important for brain function, and Duchenne boys are missing it there, too. This may lead to non-progressive mental retardation and behavioral problems which demand special attention and possibly special education.

Genetics. Duchenne muscular dystrophy is one of the most frequent hereditary diseases in humans and mammals. About one in four thousand boys, independent of their ethnic origin, are born with this disease which is caused by a mutation or damage of the Duchenne or dystrophin gene. The dystrophin gene was found or localized on the X-chromosome and its structure was determined in 1986. With about 2.5 million base pairs or genetic letters, it is the longest gene ever detected, 0.84 mm long when stretched out. But only 13,973 base pairs contain coding sequences, the information for the synthesis of the dystrophin protein. These active base pairs are grouped into 79 regions called exons. The much longer regions between the exons are the introns.

In addition to their Y-chromosome, boys have only one X-chromosome in each of their body or somatic cells. Therefore, a damaged dystrophin gene on the X-chromosome cannot be compensated for, thus, the disease manifests itself. In contrast, women have two X-chromosomes in their somatic cells. Therefore, an intact dystrophin gene on one of their X-chromosomes can compensate for a damaged gene on the other X-chromosome. Consequentely, women, even if they have a mutated dystrophin gene, generally do not show any clinical symptoms of the disease. This means that Duchenne muscular dystrophy is inherited by the X-chromosomal recessive, or sex-linked mode and the disease is transmitted to the next generation by unaffected mothers, the genetic carriers. The risk of their sons to inherit the mutated gene and to be affected by the disease and the probability of their daughters to inherit the same mutation and thus to be carriers is 50% in both cases. These risks remain the same for all following children in a family, they are not lower in families who already have one child with Duchenne dystrophy. In fact, there are many families with two and even more affected boys. On the other hand, even in families where the mother is a carrier, the disease might have been unknown because no brothers or uncles were affected or the disease was misdiagnosed in the past.

If there is only one affected boy in the family, it is not known whether the mother is a carrier or not. In these cases, the disease may have been caused by a new mutation, i.e., a damage of the gene in the fertilized egg cell. It is also possible that the mother has a germline mosaic, i.e., that several egg cells of the mother carry the mutated gene, which is a consequence of a mutation early in the development of the mother. Therefore, even in these sporadic cases, the risk of having another affected son is increased to about 7%.

Girls with Duchenne dystrophy. Girls or women with muscular dystrophy can sometimes have a form of Duchenne muscular dystrophy (e.g. manifesting carriers). In these girls, the disease can range from as severe as Duchenne in a boy to a milder Becker-like disease. About 10% of girls with a diagnosis of limb-girdle muscular dystrophy have instead a dystrophinopathy with mutations in the dystrophin gene. Therefore, before girls with Duchenne symptoms are treated like Duchenne boys, a precise genetic and clinical diagnosis has to be established.

Pathogenesis. The genetic information of the dystrophin gene specifies the protein dystrophin. This very large linear protein consists of 3,685 building blocks or amino acids, it is 125 nanometers (millionths of a millimeter) long. In other words: 8,000 dystrophin molecules arranged head to tail would just cover one millimeter! Dystrophin is located on the inner side of the muscle cell membrane and, together with several other anchor proteins, is responsible for the mechanical stability of the muscle cells.

In about 60% of the Duchenne boys, parts of the dystrophin gene are missing, their gene has a deletion, and in 5%, some regions are duplicated. The genes of the remaining 35% of patients have changes of single base pairs, so-called point mutations, or very small deletions or duplications.

The mutations may or may not disrupt the normal reading mechanism of the genetic information. If it is disrupted – frame-shifted -, then the dystrophin protein will be entirely absent or non-functional in skeletal muscle: this leads to the severe form Duchenne: the muscle fibers are degraded and replaced with fat and connective tissue followed by loss of function. When the reading frame is not disrupted in spite of a deletion or duplication – still in-frame -, then the dystrophin protein may be longer or shorter or its amount reduced: it is only partly functional and this leads to the clinically milder Becker form of muscular dystrophy.

Therapeutic research. (Updated in September 2002.) The aim of an effective and long-lasting therapy is gene therapy to transfer the active parts, the cDNA, of the intact dystrophin gene or of parts of it into the muscle cells or to repair the damaged gene. Another way is a possible drug therapy to avoid the consequences of the missing dystrophin with more conventional medical methods. The direct application of the protein dystrophin by injection into the muscles or through the blood stream is ineffective, as the large protein cannot cross the cell membranes. Dystrophin administration by mouth is also ineffective because the digestive system would destroy it completely.

A gene therapy for Duchenne muscular dystrophy has to overcome a number of difficulties: The newly introduced gene must become active only in the diseased striated muscle cells. The newly synthesized dystrophin must be anchored on the inside of the muscle cell membrane in its natural arrangement. The new dystrophin must not be attacked and thus be rejected by the immune system. And, for practical reasons, an application of the therapeutic gene material through the blood circulation should be possible as otherwise the heart and respiratory muscles could not be reached.

The first genetic therapy approach at the beginning of the 90s was the transfer of healthy immature muscle cells with an intact dystrophin gene, myoblasts, by multiple injections into the diseased muscles. This myoblast transfer technique was effective in newborn dystrophic neonatal mdx mice without a normal immune system. Subsequent trials with Duchenne boys, however, have shown that these animal experiments could not be repeated with humans.

In several research laboratories, the transfer of the active parts of the dystrophin gene, its cDNA, into the muscle cells is studied by using viruses as transport vehicles, or vectors. Especially adeno viruses, which normally cause only a common cold, and the smaller adeno associated viruses are used for transporting the full-length or the shortened cDNA. These so-called mini genes lead to the synthesis of shortened dystrophin which would change the Duchenne dystrophy into the more benign Becker dystrophy. In order to avoid an immune reaction against the vector, in some experiments all genes of the virus are removed which give rise to viral proteins. Studies with dystrophic mdx mice have shown that these techniques could also be successful in humans under the condition the the expected immnune defense against the newly made dystrophin could also be avoided.

There are other avenues of research: Plasmids can be used as vectors, they are genetic material from bacterial cells without proteins. They also can transport the active parts of the dystrophin gene. Stem cells among myoblasts or from the bone marrow of normal mice can migrate to the damaged parts of the muscles and give rise to new muscle cells which then contain the normal gene. Specific short synthetic genetic sequences, so-called oligonucleotides, can be used to repair some small mutations of the dystrophin gene or to remove entire introns flanking certain deletions in order to restore the disturbed reading frame. This exon skipping technique gives rise to shortened dystrophin which however is still sufficiently functional to lead to a slower progressing dystrophy. Experiments in muscle cell cultures and with mdx mice gave already positive results. The dystrophin-like protein utrophin, which is present in small amounts also in Duchenne children, can, at least in mice, compensate for the function of the missing dystrophin. Studies are underway to upregulate, i.e., to enhance the activity of the utrophin gene with potential drugs. The absence of dystrophin disturbs also the complicated network of many other proteins which is necessary for normal muscle function. With a new technique, expression profiling, the activities of thousands of genes for muscle proteins can be studied simultaneously.

A whole series of clinical trials with Duchenne patients are already being performed, among them are gene transfer studies with plasmids and trials of substances like creatine, prednisone and many others. Some of these studies are organized by the Cooperative International Neuromuscular Research Group (CINRG) in Washington with participation of clinical centers in several countries.

This summary demonstrates that a therapy for Duchenne muscular dystrophy is the subject of active research projects in many laboratories. But the time to find a cure needs to be shortened with more laboratories becoming involved, and this depends on more financial support. Time is of the essence for children who become weaker every day.

Aim: best possible state. The children with this disease now have a much greater chance than ever before that an effective cure will be found during their lifetime. For this reason, every effort should be made to keep the muscles of all Duchenne boys remain in the best possible state, because a future effective therapy, although most likely to be able to stop the further progression of muscle wasting, will quite certainly not cause the regrowth of muscles that have already been lost.

Medical and Social Management of Boys
with Duchenne Muscular Dystrophy

Family doctor. The family will need a long-term positive relationship with a pediatrician or family doctor who should be available for consultations, to supervise any medical treatment, and to work together with the physiotherapist and other experts, like a psychologist, his patient might need. It would be ideal if such a doctor had special knowledge of muscular diseases through experience with other Duchenne boys or through special training. S/he should know the colleagues of the next university center for muscular diseases and the Duchenne patient and parent organizations of his/her country and s/he should be open to advice from experts if that is necessary to care for his/her patient.

Weight control. Nutrition should be well-balanced and high in proteins and vitamins and low in fats. Grand parents and other visitors who are sorry for the “poor” child should understand that chocolates, sweets, and similar non-essential foodstuff are not in the interest of the child. Overfeeding causes obesity and thus constitutes an unnecessary strain for the muscles and the heart which are already weak. And as long as the boy is able to walk, he should be on his feet as often as possible.

Risks of anaesthesia. When a child with Duchenne muscular dystrophy is subjected to general anaesthesia, a number of serious problems may arise. These risks can be minimized by choosing the optimal combination of anaesthetics, careful evaluation of the child’s respiratory and cardiac functions, and close monitoring both during and after the operation. The anaesthetics should definitely not include the muscle relaxant succinylcholine and the inhalation agent halothane as these drugs may provoke life threatening complications including a syndrome called malignant hyperthermia, enhanced muscle breakdown (rhabdomyolysis), and heart rhythm disturbances.

Non-depolarizing muscle relaxants like vecuronium, atracurium, and mivacuronium can be used safely albeit at a reduced dose. Enflurane and isoflurane instead of halothane should better be avoided. The dosages of all other anaesthetics have to be carefully chosen as all of them decrease cardiac function. In children with muscular dystrophy, cardiac function is often already compromised especially at more advanced stages of the disease.

As a result, it is important – and for large operations even mandatory – to perform extensive preoperative monitoring. Depending on the specific situation, this screening may include a cardiac ultrasound, an electrocardiogram, pulmonary function tests, as well as blood gas analyses. It is thus of utmost importance to inform the anaesthesiologist as early as possible of the medical history of the child.

Individual treatment: The possibilities of treating Duchenne muscular dystrophy presented in these guidelines neither can be nor are they intended to be a substitute for well-balanced therapeutic measures for each individual child. The application and extent of possible and obligatory therapeutic measures depend in each case on several factors which have to be considered carefully together with the boy, his family, the family doctor, and the other experts.

STAGE I
None or Very Slight Clinical Symptoms
Age up to about 3 Years

At this very early stage, when the very first clinical signs appear and a muscular disease is suspected, the establishment of a precise diagnosis for the boy is absolutely necessary. As these guidelines will be read by parents whose son most probably has been diagnosed already, it should be stressed that because Duchenne muscular dystrophy is a hereditary disease, younger boys in the same family and in those related through the mother, if she is a carrier, should also be checked for the disease. However, if the mother is proven not to be a carrier, then only her own children are at risk due to a possible germline mosaicism.

Clinical diagnosis: Children with Duchenne muscular dystrophy are born without any clinical signs or symptoms of the disease. If no special diagnostic measures for the detection of a muscle disease are undertaken, the disease often remains unrecognized until the age of two to three years or older when the grandparents, the parents, and the family doctor – often in this order! – detect the first development irregularities when the child does not start walking before 18 months, has difficulties climbing stairs, gets up from the floor with his hands climbing up his thighs, Gowers’ manoevre, and develops large or hyperthrophied calves. If no muscle disease is suspected at this stage, the families often start a diagnostic odyssey lasting many months while they consult one doctor after another unsuccessfully until they are finally able to find a specialist for neuromuscular diseases.

The optimal treatment of a child with a muscular disease, however, depends on an early and precise diagnosis. Within the group of muscular diseases there is a multitude of different forms, characterized by different severity of symptoms and progression, different modes of hereditary transmission resulting in different complications at different times: loss of muscle force, contractures, walking difficulties, spinal curvature or scoliosis, and restrictions of the pulmonary function. The differential diagnosis, i.e., the decision that the symptoms are caused by Duchenne muscular dystrophy and not by any other form of neuromuscular disease relies on the results of a number of specific diagnostic procedures.

The most simple test, which should always be performed immediately when a muscle disease is suspected, is the determination of the protein creatine kinase (CK) in the blood serum. This protein is an enzyme which plays an important role in the transfer and storage of chemical energy in muscles. When the muscle membrane is damaged as in Duchenne dystrophy, this protein and many other substances leak out into the blood stream. As creatine kinase occurs mainly in muscles, a consistently positive CK test with an activity of more than 1.000 units per liter is an indication of a dystrophic process caused possibly by Duchenne muscular dystrophy. A high CK test result alone, however, is not a definite diagnosis but signifies only that the child may have a muscular dystrophy.

Then, a number of more specific diagnostic methods are available, which should be chosen according to the individual situation. They should not frighten the children more than necessary. The recording of the electrical activity of muscles by electromyography (EMG) hurts when needle electrodes are used, and thus should not be done if a child has high serum CK activities and a muscular dystrophy is clearly suspected because of other findings such as large calves, difficulties of walking or when there are other Duchenne children in the same or closely related families. EMG scans with surface electrodes can also be used, but ultrasound imaging of the muscle gives as much information, is painless, and the children can even see their own muscles on the screen. Computer tomography scans with X-rays should not be used in children if detailed definition of muscle structure is desired, magnetic resonance imaging gives similar results without the use of damaging radiation.

In spite of the availability of genetic tests, a muscle biopsy, i.e., obtaining a sample of muscle tissue, is still necessary in most cases, unless there are other unequivocally diagnosed Duchenne children in the immediate family. But as the modern biochemical techniques need only very small amounts of tissue, a needle biopsy is considered sufficient by several investigators instead of an open biopsy. The advantage of the needle technique is that it can be done under local anaesthesia after sedation with chloral hydrate. More than one muscle sample can be obtained through the same incision and this is sufficient for the analysis of the protein dystrophin. Immunochemical tests with different antibodies allow distinction between Duchenne and other forms of muscular dystrophy (limbgirdle and Becker dystrophies).

Molecular diagnosis: In most cases, a Duchenne diagnosis can be confirmed in the leukocytes of a blood sample by genetic tests for deletions, duplications, and point mutations in the exons and sometimes in the introns of the dystrophin gene. Often, the details of the deletions allow to predict the severity of the clinical course. Following genetic counseling, the female relatives of the Duchenne boy, i.e. his mother and sisters, and the sisters of his mother and their daughters etc., can also be tested for the same deletions so that these persons at risk can be told whether they are genetic carriers of the disease or not. If the mother is shown not to be a carrier, then her sisters and other relatives are not at risk, only her daughters have a 7% carrier risk due to a possible germline mosaic.

If, as is the case in 35% of all Duchenne boys, no deletion is found and there are more Duchenne boys in the same family, polymorphic microsatellite markers or short tandemly repeated sequences (STR’s) inside the gene and in its neighborhood can show the inheritance of the gene through the family without needing to know the exact mutation itself. If a boy with clinical symptoms and high CK activities but without a family history has no deletion or duplication, then a point mutation in the dystrophin gene can be assumed. There are several methods to test for point mutations, but they are time consuming and expensive and therefore not performed regularly.

Final diagnosis: Both, biopsy investigations and genetic analyses, are generally necessary to make the diagnosis definite but a biopsy should not be necessary for a second Duchenne boy in the same family when all other clinical and biochemical data are unequivocal. But the real final diagnosis, as regards clinical severity and prognosis, must always be made by an expert on a clinical basis, because there are exceptions to the predictive value of gene tests.

If a Duchenne muscular dystrophy has become a certainty, it is important that the results of the diagnostic procedures are communicated to the parents in a compassionate way, in private, and with sufficient time so that all questions regarding the prognosis, the management of their son and the consequences for the whole family can be discussed in all necessary detail without using non-explained medical terminology.

Genetic counseling. After a child has been diagnosed with Duchenne muscular dystrophy and definitely before his parents or other relatives related through the mother decide to have more children, the family should seek genetic counseling, if possible from a geneticist specialized in neuromuscular diseases. It is obvious that the counselor should give them as much information as necessary in a language they understand so that they can make their own decisions in accordance with their plans for the future.

The precise recurrence risk for female relatives of a Duchenne boy depends on the exact diagnosis of the boy and of the carrier status of those women seeking counseling. If they have not been performed yet, the counselor will initiate these diagnostic procedures on request and ask that all medical-scientific reports are made available to him or her. The exact carrier diagnosis is essential for each woman at risk: those who have an increased risk for a child with Duchenne dystrophy should be offered prenatal diagnosis in the early stages of a possible pregnancy. At any rate, the significance of a risk, whether high or low, should be explained and it should be stressed that in spite of a low risk, it is still possible that a new child will be affected. It is also important to understand that the recurrence risk remains the same for any subsequent child in a sibship independent of whether any other child is affected or not. The counselor should help the parents in a non-directive way to reach a decision on the different options of life and family planning when faced with an increased recurrence risk.

Responsibility for mutations. Mutations occur as a consequence of the basic laws of nature. These occasional changes of genetic information were necessary for the development of life and evolution to ever more complex organisms. Most of these biological and physical processes causing mutations, like e.g. cell division and cosmic rays, cannot be altered or influenced in any way. Therefore, no person is responsible or can be made responsible for damaging mutations in his or her genes. In particular, a carrier mother is not guilty and cannot be blamed for the mutation that caused a hereditary disease like the Duchenne muscular dystrophy of her son! Such an attitude would not help at all to come to terms with the problems of the disease.

Prenatal diagnosis. The most practical and recommended procedure is chorionic villi sampling (CVS), a biopsy technique with which fetal cells are obtained from the developing placenta by suction through the cervix or the abdomen. This technique can be performed as early as the 10th week of pregnancy but has about a 1-2% risk of inducing abortion. The genetic material obtained from the fetal cells is then analyzed for the sex of the child. If it is a boy, the material is tested by molecular diagnostic methods for the same mutation as found in the first affected child.

An amniocentesis, the withdrawal of a few milliliters of amniotic fluid can be performed in the 14th or 15th week of gestation with an abortion risk of 0.5-1%. The the few fetal cells obtained either have to be grown in culture for about another 2-3 weeks before analytical techniques can be performed, or they can sometimes be used directly as explained in the previous paragraph.

Continued consultations. During the years following the diagnosis, contacts with experienced medical and social experts will be necessary at regular intervals. In these consultations, the problem of heredity and psychosocial conditions, such as upbringing, school and profession, may be discussed. The many possibilities of obtaining help should be presented. The parents need to be assisted in their first contacts with the local health authorities. The organizations for handicapped persons and their parents in the different countries can often provide direct assistance through their personal care services. It is also important to establish contacts between families who are confronted by the same problems in personal meetings or through letter services on a national and international level.

STAGE II
Slight Muscle Weakness and Beginning Restrictions of Movement
Age about 3 to 6 Years

At this early stage, the first specific symptoms of the disease manifest themselves: reduced muscle power, first restrictions of movements through the full normal range of the joints. The family pediatrician and the physiotherapist with special knowledge of neuromuscular diseases should work together and see it as their first goal to enhance and to protect the individual muscular functions of the child as long as possible. Both should involve the parents so that they themselves can perform the treatments and exercises, and above all, they should let them be the best advocates of their son because they know him best, know what he needs, what is best for him and what his possibilities and his limitations are. In many instances, they will need to make decisions in his name.

Maintenance of muscle power. According to the child’s wishes, normal physical activities should be allowed or encouraged. Exaggerated power training or high-performance sports must be avoided. Walking and other physical activities should be encouraged according to the individual possibilities of the child. This kind of physical stress is not only harmless but actually beneficial. As swimming is a useful exercise, it should be taught very early, and any style except butterfly is recommended; water temperatures between 28 and 31°C are preferable, but this is not always easy to find and not absolutely necessary. Bicycle riding on a bicycle, tricycle or on a home trainer is recommended. Ball games of any kind, including European football, are also recommended. The child should be encouraged to dress himself and to take care of his own daily needs as far as possible independently.

The boys are still children, thus all exercises should be presented in a playful environment, and they should only be performed to the extent the diminishing muscle power allows. The physical capabilities of other children should not be used as a goal to be reached by all means.

The joints especially prone to early contractures, hip, knee, and ankle, need to be fully moved in all directions during these activities. The children, especially those who are inclined to be passive, have to be “stretched”. Parents should be taught to carry out additional daily stretching exercises and incorporate them into the child’s play as much as possible as instructed by an experienced physiotherapist.

Unnecessary bedrest is to be avoided, e.g. in the case of uncomplicated fever. If bedrest should be necessary for a longer period than two days, intermittent active exercises for the pelvic girdle must be carried out. The child should be brought into upright position about 5 times daily for 5 to 10 minutes.

Physiotherapy. Although there is no consensus among the experts on the importance of physiotherapy for boys with Duchenne muscular dystrophy, physiotherapy may have a positive influence on the development of muscle weakness and delaying contractures. Physiotherapy is also necessary to develop good balance and to encourage the child in new activities.

Physiotherapy can only be effective as long as the joints are freely mobile in all directions and as long as antagonist muscles are not shortened. Already at this early stage, at an age of 4 to 5 years, slight restrictions of the range of motion of the joints become apparent: hip, knee and ankle joints can no longer be over-extended normally and also hip adduction is affected, i.e., the legs cannot be closed completely. In time, the muscles become overstrained and start to deteriorate at an ever increasing pace.

Night splints. There is a controversy whether ankle braces or night splints should be recommended at this stage of the disease, since retardation of the development of contractures has not been scientifically proven. Their use can be a burden for the boy and his family. However, if they are used early on and regularly, the child may get used to them and the braces may possibly delay the development of foot contractures.

Early orthopaedic intervention. When the doctor and, above all, the physiotherapist detect these first signs of a deterioration of the range of motion of the joints in both legs, it is possible to release the contractures by an early orthopaedic intervention. The objective of this early operation is to preserve the boy’s walking ability without technical aids and thus his independence for as long as possible. As the development of contractures of the feet, knees, and hips are retarded for several years, there is much less need for physiotherapeutic stretching exercises, and many of the children have been able to walk without assistance longer than without the operation. At the end of their independent walking ability, so operated children can be fitted with orthoses, as described in stage IV, with none or only minor additional surgical adjustment.

In effect, there are two approaches of orthopaedic intervention which reflect different philosophies: the more conservative approach with a minimum of surgery at the end of the independent ambulatory phase at about 10 years, or the early treatment with comprehensive surgery at about 5 years, when symptoms are hardly seen, but with less physiotherapy during the independent ambulatory phase.

If the parents decide to have the early operation performed, it is obvious that this should only be done in centers with extensive experience of the surgical procedure and only when the proper follow-up examinations are available.

In these early orthopaedic operations, the beginning deterioration of over-extension capacity of the hip, knee, and ankle joints, as well as the deterioration of the pelvic range of motion, are fully corrected by the release of hip, knee, and ankle contractures and the partial removal of the iliotibial band, i.e., an operation on soft tissues and tendons only. Afterwards, the muscles regain their optimal work capacity. About three days after the operation, the child is able to get up from bed and walk around under supervision of a physiotherapist. The operation itself is not difficult to perform for an orthopaedic surgeon experienced in these methods. The long scars on the thighs have only minor cosmetic consequences.

Steroid treatment. Several studies over the past 10 years have shown the benefit of prednisone in Duchenne muscular dystrophy. The main problem has been the inevitable side effects, especially weight gain. Most of the problems have shown up in older children. Recently, younger children have also been treated and different schedules of treatment have been introduced to try to avert the side effects. Deflazacort, a drug similar to prednisone, has also been tested on the grounds of having less side effects.

The steroids prednisone and deflazacort can delay the muscle deterioration for several years, probably due to their anti-inflammatory effect. In a double-blind study in Germany, these two drugs have been compared with the result, that deflazacort shows less weight gain than prednisone, but more frequent development of cataracts. The dosis most probably to be recommended in the future will be 0.75 mg prednisone/kg/day or 0.9 mg deflazacort/kg/day. As the statistical evaluation of the study is not yet been completed, a definite recommendation for a medication with one of these two steroids cannot be given at this time. If parents wish to have their Duchenne son be treated with these drugs, they need to get information in which centers trials are being performed, as this type of treatment should be done only in the context of a scientific study.

Kindergarten. At this stage of their disease, Duchenne boys are only very slightly handicapped. They should go to the kindergarten in their neighborhood like the other children, too. The kindergarten teacher, however, should know about the disease so that s/he can avoid the child undergoing too much physical stress. S/he should also explain the situation to the other children who are normally quite willing to accept it and to help their friend when necessary.

STAGE III
Increasing Muscle Weakness and Contractures
Age about 6-10 Years

At this transitional stage before the loss of the independent walking ability, the main problems to face are the further decrease of muscle power and the development of increasing contractures in the muscles of the feet, legs, and hips which will make it more and more difficult for the children to maintain their balance while walking. The boys who had their beginning contractures released will have less problems than those without these early operations. Some of the following suggestions thus apply only as far as problems have to be solved.

Physiotherapy. The activities and exercises of the early phase should be continued. In order to strengthen the decreasing muscle power and to treat the contractures in the best possible way, active exercises of the affected muscles have to be carried out on a daily basis and with the parents’ help. As soon as contractures appear, an experienced physiotherapist should show the parents how to treat them twice a day by stretching the Achilles tendon, the connective tissue band from the iliac bone to the lower leg (iliotibial band), and the knee-flexors. The stretching of the muscles, ligaments, and joints should be carried out 10 to 15 times, using each time the full range of motion of a joint. These exercises should last 10 seconds each time and should be carried out slowly with the active cooperation of the child.

Furthermore, supplementary exercises are recommended: bending the upper body against a wall while keeping the feet flat on the floor; lying in prone position while reading or watching television. The equino-varus foot position has to be avoided by means of a support at the ankle joint.

If at all possible, these exercises should be incorporated into the child’s playing activities. Other activities should be considered like playful wrestling with an adult on the floor, therapeutic horseback riding, European football, basketball, gymnastic ball, and karate. These exercises enhance balance because the children have to develop compensatory movements to maintain balance while walking.

All these exercises and activities need to be carried out daily by family members and be supervised by the physiotherapist at least twice a month and by the family doctor every 3 months. The physiotherapist should also make respiratory measurements to determine a baseline and also to watch for the signs that indicate the need for the first or further orthopaedic interventions.

Orthopaedic measures. When the child starts walking on tiptoes, i.e., develops an equino-varus position of the feet, a transfer of the tendon of a lower-leg muscle (tibialis posterior) onto the forefoot from above can be useful. This muscle normally moves the foot downward. The transfer counteracts the formation of the equino-varus deformity and permits the child to wear normal shoes. This operation can be performed with the later operations on the hip, knee, and ankle joints.

Light-weight shoes with profiled soles are useful so that the child will not fall on slippery floors. However, special or orthopaedic shoes are not recommended at this stage.

School: As most Duchenne boys are as intelligent as other children, they can and should attend a regular school. Here again, the teachers should let all pupils and their parents know what kind of disease Duchenne muscular dystrophy is, that it is not contagious and that to have such a disease is neither the fault of the child nor of his parents.

All children should know that their weak friend sometimes needs help but only as much as necessary. It is important that Duchenne children are allowed to do tasks which they are still able to perform like writing independently. If writing by hand becomes too difficult, a computer should be made available to them. To participate in sports activities will be difficult but they should not be excluded completely from competitive games or other activities, e.g., they can play the role of referee.

If at all possible, the class room should be easily accessible by ramps or an elevator wide enough for a wheelchair. The same is true for the toilet rooms. It is recommended that always one of the older students is made responsible to take special care of the handicapped child for one particular day.

Psychological counseling. At the age of about 8 to 10 years, and sometimes earlier, the children become aware what kind of disease they have and that there is no cure. When children start asking about death and dying, it is less dramatic if this is handled at home or in school as a subject of general interest that concerns not only a child with a dangerous disease. In many countries, conscientious objectors of military service have to provide social services, these young men are often the best and most dedicated helpers of handicapped persons. At this stage, they can become an advocate for the child and might be available for difficult discussions, too. In some cases the parents might wish to have these questions answered by a psychologist, and they themselves might also need professional counseling to be able to better cope with these questions and problems.

STAGE IV
Reduced Walking Ability
Age about 10-14 Years

In spite of all management efforts, the deteriorating muscles will make it more and more difficult for the child to keep his balance. Independent walking will sooner or later become impossible due to the development of contractures and loss of muscle strength. In order to maintain the boy in an optimal condition as long as possible, his walking and standing ability can be extended for a few years by the use of long leg braces, also called orthoses or calipers. In most cases, an orthopaedic intervention will be necessary before the orthoses can be used.

The child walks with stiff legs in the long leg braces which means that the gait in the braces is not always a practical gait for outdoor walking. He will also need an electrical wheelchair for moving over long distances. However, the braces do not only give the child the opportunity to walk indenpendently indoors. They make the care and handling more easy for the parents or his siblings because it is then not necessary to lift him when he has to go to the toilet, to the basin, to bed or to get dressed as he can stand up by himself with only a little help. Standing and walking with the braces stretches the muscles that tend to develop contractures in the legs. Therefore, it reduces the need of physiotherapy as well. For the child, it feels as a relief to be able to stand up as many times a day as he wants and to stretch the back and the legs when he would otherwise be confined to sit in a chair.

There are, however, some experts who object against using calipers because walking in them is not quite normal and, therefore, rather stressful. The use of a wheelchair is sometimes seen as the easier solution. But the positive consequences of the braces for the daily life of the child and the advantages of an early use of an electric wheelchair which allows the child to better keep up with his peers outdoors leads to the recommendation to use both, braces and wheelchair at this stage of the disease.

Operative Measures: Independent ambulation with braces or orthoses of the legs for a limited period of time can only be achieved by an operative release of the contractures at both legs provided the muscles are still sufficiently functioning for a well-balanced trunk. But even after independent walking with orthoses has been lost after some time, it is still advantageous for the boy to have joints without contractures, which considerably facilitate his daily life activities and further treatment.

Only if the children can still walk and stand each day for a few hours, positive effects on respiration can be expected and the development of contractures and spine deformation, scoliosis, will be retarded. For these reasons, the boy and his family should be interested in maintaining ambulation and standing as long as possible and the exclusive use of a wheelchair should be postponed as long as possible.

The rather simple orthopaedic operation and the fitting with orthoses should be done when the children are at the end of their walking ability (age about 10 years). Any contractures at the hip, knees, or ankles have to be released by tenotomy, i.e., release of the tendons, so that the patient can be fitted with the orthoses or calipers. These orthoses have to be individually made by a specialized orthotist or orthopaedic mechanic. A typical treatment protocol would be: day 1, admission to the hospital and moulding for preparation of the orthoses; day 2: bilateral percutaneous tenotomy of the Achilles tendon and hip flexors; day 3 to 5: bed rest; day 6: fitting the orthoses and standing with orthoses; day 7 and 8: assisted and free walking in orthoses; day 9: discharge from the hospital. It is important that bed rest during the day is kept at a minimum. There is only little pain after the operation, mainly at the heel, which can be easily controlled with the usual drugs.

The children walk in orthoses with locked knees and only on flat surfaces, they should wear them most of the day. An upper lip on the orthoses, on which the child “sits” while using them, is important for keeping balance.

Control examinations: At this phase of the disease, when the Duchenne boy often remains in a seated position for a long time, a scoliosis or spine deformity starts to develop as well as a pelvic obliquity. Now, the spine and the pelvis should be examined every 6 months so that a surgical stabilization can be considered as early as possible at the beginning of the next stage, the wheelchair stage. At these control examinations, the spine must be X-rayed from the front and from the side in an upright sitting position.

For an early detection of disorders of the pulmonary function, the vital capacity, i.e., the maximum volume of expiration after maximum inspiration, and the peak flow, i.e., the maximal forced expiratory flow, should be measured at least twice a year from the age of 9 years on.

Prevention of respiratory problems: At this point, a prophylactic respiratory exercises are recommended along with physiotherapy. This should be incorporated into the child’s play, if possible, and started before the age of 9. It is important to teach the parents how to prevent accumulation of secretions in the airways by giving manual support for coughing whenever needed (see paragraph on assisted coughing below), by letting the child change position from side to side or to the back during the night. In case that secretions have accumulated they can be removed by tapping and vibration of the chest in different body positions eventually with the head in low position. Smoking is never permitted in the presence of the child. If pulmonary infections with breathing difficulties occur at this stage, the boy has to be hospitalized immediately.

Cardiomyopathy: The protein dystrophin is not only missing from the skeletal but also from the cardiac muscles, this leads in time to a heart involvement or cardiomyopathy, and that becomes normally the most important problem in the late stages of the disease. Some Duchenne boys develop early myocardial dysfunctions before respiratory insufficiency, and it is often difficult to determine the real problem. Below the age of 14 years, about 15% have significant cardiac abnormalities. The cardiac problems of Duchenne boys, however, are alleviated by the diminishing muscle mass which reduces the load on the pumping capacity of the heart.

Most Duchenne boys do not complain about cardiac problems because they are not physically active and their other problems are greater. But every boy should be checked by a cardiologist yearly from 8 years on, with echocardiography from age 10, with ultrasound and Doppler technique to determine the myocardial contractivity from age 12. The diagnostic value of electrocardiography is limited. Before any surgery, it is important to evaluate cardiac function. Cardiac insufficiency should be treated with inhibitors of the angiotensin converting enzyme (ACE inhibitors). Steroids for treating cardiac problems are not recommended and a treatment with digoxin without careful monitoring is dangerous and can lead to severe arhythmias.

Dental problems: An imbalance between the oral muscles and an enlargement of the tongue may cause a crossbite of the molars in most Duchenne boys. As this imbalance is the result of the natural course of the disease, a correction of this particular problem is not recommended.

STAGE V
Adolescent Stage
Age about 12 to 18 Years

At this stage, the diminishing muscle power will reduce the walking ability of the boy further so that he is no longer able to walk for a longer period without assistance, and only short distances can be covered without excessive fatigue. If the child does not already have a wheelchair, the use of a wheelchair must be considered, both for outdoor activities as for indoors. Although the wheelchair is often perceived as the materialized milestone of an irreversible process, its use, which cannot be avoided, should not be considered as a catastrophe. It relieves the child of much physical stress and at this stage helps him more than it hinders him to perform his daily activities.

Most of the boys with Duchenne muscular dystrophy stop walking independently between 10 and 12 years. Those who still can walk without braces at this stage may have an intermediate form of Duchenne dystrophy or even Becker dystrophy. It is advisable then to check their original diagnosis by the modern methods.

The wheelchair: In most cases, an electric wheelchair should be used from the outset because a manual wheelchair to be powered by the boy himself might be sufficient for a few months only. However, a narrow and light manual wheelchair is recommended and helpful for moving inside the house and especially for visiting places that are not adapted for an electrical wheelchair.

Size and weight of the wheelchair as well as the configuration of the wheels and their diameter should be chosen according to body size and preferable use, for outdoors or for indoors. It should be possible to bring the back of the wheelchair with the headrest into an almost horizontal position to allow an intermittent relaxation of the spine. It should also be possible to tip both the backrest and the seat backwards in one unit. The foot rests should be adjustable individually so that the sitting position can be changed. To keep the spine as straight as possible and to avoid that the boy sits asymmetrically, the lordosis of the lumbar spine should be strongly supported and the arm rests and the control panel of the wheelchair should be close to the body. For safety and comfort reasons, the wheelchair should have a security belt with an electric tightening mechanism.

The adolescent stage is characterized by an increase of the existing contractures at the hip, knee, and ankle joints as well as by a curvature of the spine (kyphoscoliosis). Contractures of the elbows, wrists, and fingers will gradually also appear. Duchenne boys who use their wheelchair exclusively, can complain of feeling tired in the back, pressure on the buttocks, and cold feet. To some extent, this can be improved by a correction of the sitting position with cushions and by applying the electrically operated functions of the wheelchair mentioned above which allow the boy to change his position by himself as often as he wishes.

Physiotherapy: At this point, the further development of contractures of the legs constitutes a major discomfort for the boys. Virtually only the sitting position is available and he can sleep only on the sides and on the back with the knees bent and supported by pillows. Therefore, further stretching exercises for the muscles and tendons should be carried out regularly to retard the progression of the contractures also in the arms.

The physiotherapist should accompany the boy and follow up on the therapeutic measures taken which can increase the life expectancy and quality considerably: scoliosis operation, and mechanical ventilation. The role of the physiotherapist is also to prepare the boy and his parents for these interventions.

The young man is now old enough to decide himself how to be treated and to be the master of his own time. Together with the specialists, he should decide how to integrate the physical exercises into his daily life activities. He should have enough time to develop and pursue his social and intellectual abilities in a way that would allow him to compensate as much as possible for his physical disability.

The aim of physiotherapy is to maintain the physical independence as far as possible by physical exercises and by accepting all offers of help. An ever growing series of technical aids is able to compensate for weakness and disabilities. As the physiotherapist is often closer to the family than the other medical specialists, s/he can play a mediating role, advising when it is time for particular interventions, e.g. the use of mechanical respiratory aids by intermittent positive pressure breathing (IPPB) or aids for keeping the airways free from secretions such as continuous positive airway pressure (CPAP). S/he also should teach the parents assisted coughing techniques to remove secretions and to overcome life threatening respiratory incidents.

Respiratory management: The prognosis for Duchenne boys, i.e. his future life, depends to a large extent on his respiratory function. Inspiratory and expiratory muscles are affected by the disease and respiratory problems will occur with or without additional spinal deformities. The consequences are sleep breathing disorders and frequent respiratory infections.

The parents and their son should understand the symptoms associated with respiratory dysfunction and, when they are present, immediately contact the medical experts to evaluate the need for respiratory treatment. Respiratory dysfunction starts with symptoms of nocturnal hypoventilation: insomnia, nightmares, frequent calls at night, nocturnal and morning headaches, daytime fatigue and sleepiness, decrease of intellectual performance, loss of appetite, weightloss, frequent respiratory infections, and cardiac rhythm abnormalities. Arterial blood gases, vital capacity, and respiratory muscle strength should be measured, and breathing during sleep monitored. Symptoms of underventilation with muscle strength less than 30%, vital capacity less than 50% or 1.5 liters, a partial oxygen pressure of less than 75 mm Hg and/or a partial carbon dioxide pressure of more than 45 mm Hg and/or nocturnal oxygen desaturation of less than 90% are indications for beginning treatment. Swallowing disorders and associated factors like obesity and smoking put a patient at higher risk.

Treatment should begin with the education of the parents and their son to prevent respiratory infections, to control weight, to avoid intestinal problems such as constipation, and to learn assisted coughing and secretion removal techniques. Respiratory assistance should be started at night with a ventilator through a nasal mask, and later, when needed, daytime ventilation using a mouthpiece can be added. In the earlier stages, nocturnal ventilation is sufficient to eliminate symptoms of underventilation. Intermittent ventilation through a mouthpiece on demand during the day (4 to 5 times per minute) with the ventilator installed on the wheelchair is very beneficial at later stages. Preventive ventilation before symptoms occur is not effective.

Treatment of underventilation with oxygen alone is not indicated and can be dangerous!

Tracheostomy ventilation, i.e. breathing through an opening in the windpipe, is recommended when patients have little respiratory autonomy and show poor results of non-invasive ventilation or when swallowing disorders lead to chronic aspiration of saliva and food. Tracheostomy is very effective, but it is not usually reversible and increases drastically the dependency on care which might not be available in every case.

Assisted coughing: The clearing of the lungs from secretion normally achieved by coughing is difficult for the Duchenne boys whose abdominal and respiratory muscles are severely deteriorated. Specially trained physiotherapists know how to assist him and should show the parents or other caregivers this technique which may be lifesaving in an emergency. This is very important as the inability to cough in an emergency leads quite often to death by suffocation.

Operative correction of scoliosis: When a Duchenne boy starts to use the wheelchair predominantly, the further weakening of the muscles of the back leads to a progressive deformation of the spine, i.e., a scoliosis develops. This deformation cannot be corrected by corsets but only by surgical stabilization. Among the different surgery techniques, the most often used are the Luque and Cotrel-Dubousset techniques in which the spine is stabilized by steel rods attached to the vertebrae with loops of wire or screws. This rather extensive operation has become routine and up to 80% of the Duchenne boys in the developed countries are operated in this way. These operations should only be performed in centers with experience and only when follow-up over several years is assured.

At the time of spine correction, Duchenne boys have a cardiomyopathy though mostly without clinical signs of a cardial insufficiency. Before surgery, it is not possible to assess the real cardial stress tolerance caused by the operation. It is noteworthy that during spine surgery, the boys do not usually show left ventricle problems but rather signs of a right ventricle insufficiency. They also have a platelet function deficiency in spite of a normal bleeding time and therefore need extensive blood transfusion during surgery and substitution with the protease inhibitor aprotinin.

After the operation, the boy does not need a corset. The operation generally has no major influence on the growth as the spine has normally stopped growing at an age of 12 to 14 years. On the contrary, as the spine is straightened by the operation, the children become taller. The majority of boys and their parents have positively evaluated the sitting position, the cosmetic improvement, and the quality of life after the surgical correction of the spine. More than 90% would give their consent for this rather extensive operation again.

The best time for the operation is, when the angle of the spinal curve while sitting just exceeds 20°. A preventive operation before the onset of scoliosis is not recommended. Prerequisites for the operation are a good general condition and a minimum vital capacity of about 30% of normal. The extent of the curvature, however, is normally not the limiting factor for the operation. The correction of scoliosis by spine surgery does not necessarily increase vital capacity. However, the children can breathe better and often need less assisted respiration afterwards. In addition, spondylodesis (spine fusion) during the operation will help to minimize the secondary chest deformities. It is important that the scoliosis operation is followed up by adapting the wheelchair and the height of the table to make sure that the young man can maintain use of his hands for eating and writing as he did before the operation.

School and professional training: There are many Duchenne boys who attend high school or even university. If the proper technical aids are available, there are practically no limitations for a challenging education as long as no physical power is required. Computer programmer always comes first as a possible profession, but there are many others like translators, interpreters, teachers, attorneys, telephone operators, secretaries, writers, even politicians. The parents and the whole family should encourage and help the boy if he wishes to pursue a particular professional education. In many countries, financial assistance is available for the training of handicapped persons.

Psychological counseling: At the onset of puberty, Duchenne boys become aware more than before that they will not be able to lead a normal emotional and sexual life. Here again, the services of a professional psychologist will be needed.

STAGE VI
Adult Stage
Age more than about 18 Years

At this stage, most of the skeletal muscles have deteriorated and the young man depends on a number of technical aids including continuous mechanical respiration. In spite of this situation, with the proper help, they can, if they wish and if they have access to all necessary technical aids, lead a meaningful and even productive life. But long-term personal assistance would be very helpful if it is available for those who wish to become independent of their parents.

Specific problems. The problems that might appear at this stage are: difficulties in sitting upright in the wheelchair and in controlling the head or difficulties in operating the joystick of the wheelchair with the hands. These problems can usually be solved by technical adaptations of the wheelchair. Difficulties in operating the keyboard of a computer can also be solved by using a minikeyboard that can be held and operated in one hand. In the event of swallowing difficulties a correct positioning for the head has to be ensured; it may be necessary to feed mashed or liquid food. These problems can aften be solved by proper ventilation, if necessary after tracheostomy. Sleeping problems caused by a lack of mobility of the body may be improved by the use of foam rubber mattresses or a special air mattress, whose side chambers can be inflated alternately, and devices which avoid the pressure of the blanket on the feet like a foot cradle. Transportation problems can be overcome with hydraulic lifting devices in the toilet and bathroom; special beds which can be tilted electrically are often indispensible.

The young men are adults. Although most of the decisions concerning his life had to be made by his parents, the young man with Duchenne muscular dystrophy is now an adult. That means, he himself can and should decide how and to what extent to accept the suggestions of his medical and social advisers. This is especially important when decisions are due whether to begin mechanical ventilation with or without a tracheostomy. Even the most important decision, namely whether to ask for medical emergency measures, should they become necessary, should be left to the young adult himself. In fact he should make his views known and give the corresponding instructions in a legal binding way before emergencies arise.

School, education, professional life. As mentioned above, there are practically no limits for a well-maintained young man with Duchenne muscular dystrophy, who has all necessary technical aids, to attend school or university or to pursue a profession as long as no physical power is necessary. In most countries there are laws which prohibit the discrimination of handicapped people, and that means that all physical barriers which would impede access must be removed and all help provided so that people with Duchenne muscular dystrophy can participate in all life activities. However, an excellent education does not automatically guarantee an adequate working place or professional position. It will be difficult to find work at all because competition will be severe and rejection may have serious consequences. Unpaid or underpaid work may often be better than no work at all.

Sexuality: This is a very difficult subject because Duchenne boys are sexually quite normal but their handicap makes it almost impossible for them to live a normal sexual life. Not only these problems make it mandatory that the young adults have enough privacy. This would be easier to achieve if they were able to live outside their parents’ home in an environment which encourages independent living and partnerships. Although it is still an exception, marriages or partnerships between a man with Duchenne dystrophy and a non-handicapped woman are known. If the female partner is not a Duchenne carrier herself, their children have no increased risk for Duchenne dystrophy. The affected man would transmit his intact Y-chromosome to all of his sons, thus the sons would be completely free of the disease and also would not transmit it further. All daughters would receive the X-chromosome with the mutation and therefore be carriers who would then transmit the mutated gene to their children with a risk of 50%.

Conclusion and Outlook

Duchenne muscular dystrophy has always been with mankind and also with all animals which have muscles. It got its name in the last century after the French physician Duchenne de Boulogne described it in 1868. From the mode of inheritance, it was known at the beginning of this century that a defect on the X-chromosome was responsible for the disease, but only in 1986 was the gene itself, the dystrophin gene, identified and shortly afterwards the protein dystrophin, which is missing in Duchenne boys, characterized. The fast pace of genetic research gave rise to an optimism that a gene therapeutic approach would soon be able to replace the gene and the protein and thus cure the disease.

This optimism was premature. The first clinical studies in 1991 with a gene replacement method, myoblast transfer, showed that a technique which looks promising in laboratory animals like mice was ineffective in Duchenne boys. Now, more than a decade after the detection of the gene, there is still no therapy, neither for Duchenne dystrophy nor for any other hereditary disease like cystic fibrosis. A whole series of gene transporters, viruses or other vectors, are being studied in dystrophic mice and dogs. But before they can be injected into the muscles of children, it has to be shown that they are safe and effective first in mice, then in dogs and finally in Duchenne children, i.e., they must cause the re-appearance of dystrophin at the inner face of the muscle membrane and improve the muscle function considerably. The next step would be the development of a method that would allow the application into the blood stream so that all muscles, also those of the heart and the lung, could be reached. All these studies will need time-consuming experiments with large groups of Duchenne boys. And last but not least, the technical and economic problems of large-scale manufacture of the therapeutic agent must be solved.

All these requirements must be considered and evaluated before it is possible to make any prediction of how long it will take until a safe and effective therapy becomes available for children with Duchenne muscular dystrophy. The answer to this question is the most important one for the parents and their sons. It will probably take several years, more like ten years than five, until Duchenne muscular dystrophy is conquered. This is not what has been hoped for, that is the negative side of this difficult problem, the positive is that there are more and more capable and dedicated researchers in laboratories all over the world working on a cure: therefore, it is certain that an effective therapy will be there, sooner or later.
Text prepared by Dr. Günter Scheuerbrandt
Im Talgrund 2, D-79874 Breitnau, Germany
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